Metabolic syndrome, also known as syndrome X, is now a global health problem of epidemic proportions. This syndrome denotes a collection of obesity-associated pathologies that include insulin resistance, hyperinsulinemia, enhanced hepatic glucose uptake into the skeletal muscle and fat, elevated levels of circulating free fatty acids, and increased fat accumulation in insulin target tissues. The resulting hyperglycemia, dyslipidemia and hypertension also lead to endothelial dysfunction and thus place metabolic syndrome patients at high risk for atherosclerosis. There is an urgent need for elucidation of the molecular events that result in the development of the metabolic syndrome, and for the identifying novel strategies for prevention and therapy of the disease.
The molecular events that result in the development of the insulin resistance that underlie the metabolic syndrome remain incompletely understood, but available information suggests that the nuclear hormone receptors termed peroxisome proliferator activated receptors (PPARs) play central roles in the process. PPARs are ligand activated transcription factors that appear to function as “lipid-sensors”. Like other members of subclass 1 of the superfamily of nuclear hormone receptors, PPAR s interact with the retinoid X receptor (RXR) to form heterodimers that bind to PPAR response elements in regulatory regions of specific target genes. Binding of cognate ligands to these heterodimers result in receptor activation and in upregulation of transcription of the target genes. PPARs thus induce metabolic cascades that upregulate lipid storage, transport, and homeostasis. Three PPAR subtypes, encoded for by three separate genes, are known to exist: PPARα, PPARδ, and PPARγPPARα is expressed in liver, heart, muscle and kidney, where it regulates fatty acid catabolism. PPARγ is expressed predominantly in adipose tissue and macrophages, where it is involved in adipocyte differentiation, regulation of sugar and lipid homeostasis, and control of inflammatory responses. Thiazolidinediones, synthetic compounds that activate PPARγ are in current use as antidiabetic drugs.